Pharmaceutical combination

Abstract

This invention relates to a combination product or medicament comprising at least one novel substituted pyrrole derivative and one or more dyslipidemic agents, antiobesity agents, antihyperglycaemic agents, anti-inflammatory agents or mixture thereof. Also provided herein are the pharmaceutical compositions comprising at least one novel substituted pyrrole derivative and one or more dyslipidemic agents, antiobesity agents, antihyperglycaemic agents, anti-inflammatory agents or mixture thereof and optionally together with at least one pharmaceutically acceptable carrier, and methods for the treatment or prophylaxis of cardiovascular diseases, Alzheimer's disease, obesity, diabetes or inflammatory diseases comprising administering to a mammal in need thereof therapeutically effective amounts of combination pharmaceutical composition comprising at least one novel substituted pyrrole derivative and one or more dyslipidemic agents, antiobesity agents, antihyperglycaemic agents, anti-inflammatory agents or mixtures thereof.

We claim: 
     
         1 . A combination product or medicament comprising at least one substituted pyrrole derivative having the structure of Formula I, 
       
         
           
           
               
               
           
         
         pharmaceutically acceptable salts, pharmaceutically acceptable solvates, prodrugs, metabolites, polymorphs, tautomers, racemates, pure enantiomers, diastereoisomers or N-oxides thereof, wherein: 
       
       
         
           
           
               
               
           
         
         R 1  is C 1 -C 6 , C 3 -C 6 , or optionally substituted phenyl (wherein up to three substituents are independently selected from halogens, C 1 -C 6  alkyl, cyano, or C 1 -C 3  perfluoroalkyl); 
         R 2  is optionally substituted phenyl (wherein up to three substituents are independently selected from cyano, acetyl, or optionally substituted amino, wherein up to two amino substituents are independently selected from C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, acetyl, or sulfonamide); 
         R 3  is optionally substituted C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl (wherein substituents are independently selected from halogens, hydroxyl, C 1 -C 3  alkoxy and protected hydroxyl); 
         R 3  is also —NR 8 R 9 , wherein R 8  and R 9  are optionally substituted C 1 -C 6  alkyl 
         (wherein the optional substituent(s) is/are selected from halogens, hydroxy, C 1 - 3  alkoxy and protected hydroxyl); 
         R 4  is 
       
       
         
           
           
               
               
           
         
         wherein R 5  and R 6  are independently hydrogen, C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl, optionally substituted aryl or aralkyl, wherein the substituents are selected from halogens, cyano, optionally substituted C 1 -C 6  alkyl (wherein up to two substituents are independently selected from hydroxyl, protected hydroxyl, and halogen(s)), optionally substituted amino (wherein up to two substituents are independently selected from SO 2 R 7 , COR 7 , or CONHR 7 , wherein R 7  is C 1 -C 6  alkyl or aryl), or acetyl, trifluoromethyl, or C 1 -C 6  alkoxycarbonyl, or R 5  and R 6  together form a 5-7 membered ring with one or more optional heteroatoms wherein the hetero atom(s) are independently selected from nitrogen, oxygen and sulfur, or R 4  is an optionally substituted mono-, bi- or tricyclic heterocycle having one or more hetero atom(s) wherein said hereto atom(s) is/are independently selected from oxygen, nitrogen and sulfur, and the optional substituents are independently selected from halogens, hydroxy, protected hydroxyl, C 1 -C 3  alkoxy, cyano, C 1 -C 3  perfluoroalkyl, C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl, aryl or optionally substituted aralkyl wherein the substituents are independently selected from halogens, hydroxy, protected hydroxyl, C 1 -C 3  alkoxy, cyano, or C 1 -C 3  perfluoroalkyl, and the pharmaceutically acceptable salts, tautomers, racemates, pure enantiomers or diastereoisomers, and solvates of the compounds of Formula I, 
         with the proviso that R 2  is phenyl only when (1) R 5  or R 6  is C 3 -C 6  cycloalkyl or phenyl substituted with acetyl, alkyl, cycloalkyl, hydroxyalkyl, alkylsulfonamido, acetamido or (2) when R 5  and R 6  together form a 5-7 membered ring with or without one or more heteroatoms wherein the hetero atom(s) are selected from nitrogen, oxygen and sulfur or (3) when R 5  or R 6  is aralkyl optionally substituted with halogens, cyano, C 1 -C 6  alkyl, C 1 -C 6  halogenated alkyl or (4) when R 4  is optionally substituted mono-, bi- or tricyclic heterocycle having one or more hetero atom(s) (wherein the optional substituents are independently selected from halogens, hydroxy, protected hydroxyl, C 1 -C 3  alkoxy, cyano, perfluoroalkyl of one to three carbon atoms, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, aryl, or optionally substituted aralkyl (wherein the aralkyl substituents are independently selected from halogens, hydroxy, protected hydroxyl, C 1 -C 3  alkoxy, cyano, or C 1 -C 3  perfluoroalkyl; and 
         one or more dyslipidemic agents, antiobesity agents, antihyperglycaemic agents, anti-inflammatory agents or mixtures thereof. 
       
     
     
         2 . The product or medicament according to  claim 1 , wherein:
 (a) dyslipidemic agents are selected from cholesteryl ester transfer protein inhibitors, fibric acid derivatives/fibrates, antihypertensive agents, bile acid sequestrants, Acyl CoA -cholesterol acyltranferase inhibitors, cholesterol absorption inhibitors, bile acid reabsorption inhibitors, triglyceride synthesis inhibitors, MTP inhibitors, transcription modulators, squalene epoxidase inhibitors, LDL receptor inducers, platelet aggregation inhibitors, fish oils, omega 3 fatty acids, farnesoid X receptor agonists, liver X receptors, squalene synthase inhibitors, microsomal triglyceride and guggul lipids;   (b) antiobesity agents are selected from 5-HT reuptake inhibitors, pancreatic lipase inhibitors, cannabinoid antagonists and recombinant human ciliary neurotropic factors;   (c) antihyperglycaemic agents are selected from insulin sensitizing agents/PPAR agonists, sulphonyl ureas, alpha glucosidase inhibitors, DPP4 inhibitors and GLP-1 agonists; and   (d) anti-inflammatory agents are selected from β2 agonists, COX-2 inhibitors, 5-lipooxygenase inhibitors, phosphodiesterase IV inhibitors, MMP inhibitors, TNF-α inhibitors, caspase inhibitors, p38 mapkinase inhibitors, VLA-4 antagonists and PAF antagonists.   
     
     
         3 . The product or medicament according to  claim 2 , wherein:
 cholesteryl ester transfer protein inhibitors are selected from torcetrapib, JTT-705 or CP 532623;   fibric acid derivatives/fibrates are selected from etofibrate, fenofibrate, clofibrate, gemfibrozil, bezafibrate, ciprofibrate, clinofibrate or theofibrate;   antihypertensive agents are selected from amlodipine, its salts and prodrugs thereof, lomerizine, isradipine, lacidipine, lercadipine, manidipine, benidipine, cilnidipine, felodipine, bepridil, diltiazem, fendiline, nicardipine, nimodipine, nilvadipine, nitrendipine, nisoldipine, zonisamide or nifedipine;   bile acid sequestrants are selected from cholestyramine, colestipol, covesevelam, probucol or nicotinic acid;   Acyl CoA-cholesterol acyltranferase inhibitors are selected from F-12511 or NTE-122;   cholesterol absorption inhibitors are selected from ezetimibe;   MTP inhibitors are selected from, batimastat (BB-94), marimastat (BB-2516), prinomastat (AG3340), BAY 12-9566 or CGS27023A;   5-HT reuptake inhibitors are selected from fluoxetine, femoxetine, fluoxetine, sertraline or sibutramine;   pancreatic lipase inhibitors are selected from orlistat;   cannabinoid antagonists are selected from rimonabant;   recombinant human ciliary neurotropic factors are selected from axokine;   insulin sensitizing agents/PPAR agonists are selected from pioglitazone, rosiglitazone, or muraglitazar;   sulphonyl ureas are selected from metformin;   alpha glucosidase inhibitors are selected from acarbose, miglitol, miglustat or voglibose;   DPP4 inhibitors are selected from acarbose, miglitol, miglustat or voglibose;   GLP-1 agonists are selected from exendin-4, liraglutide or CJC-1131;   β2 agonists are selected from albuterol, formoterol, terbutaline or metaproterenol;   COX-2 inhibitors are selected from parecoxib, valdecoxib or rofecoxib;   5-lipooxygenase inhibitors are selected from zileuton or atreluton;   phosphodiesterase IV inhibitors are selected from RBx-11082, cilomilast or roflumilast;   MMP inhibitors are selected from batimastat (BB-94), marimastat (BB-2516), prinomastat (AG3340), BAY 12-9566 or CGS27023A;   TNF-α inhibitors are selected from infliximab, etanercept, D2E7 or CDP 571;   caspase inhibitors are selected from pralnacasan (Vx-740);   p38 mapkinase inhibitors are selected from Vx-745, BIRB-796, RWJ-67657 or SB-239063;   VLA-4 antagonists are selected from clafrinast or RBx-7796; and   PAF antagonists are selected from apafant, ibudilast, lexipafant, rupatadine or ginkgolides and derivatives thereof.   
     
     
         4 . The combination product or medicament of  claim 1 , wherein the at least one substituted pyrrole derivative and the one or more dyslipidemic agents, antiobesity agents, antihyperglycaemic agents, anti-inflammatory agents or mixtures thereof are administered separately. 
     
     
         5 . The combination product or medicament of  claim 1 , wherein the at least one substituted pyrrole derivative and the one or more dyslipidemic agents, antiobesity agents, antihyperglycaemic agents, anti-inflammatory agents or mixtures thereof are administered simultaneously. 
     
     
         6 . The combination product or medicament of  claim 1 , wherein the at least one substituted pyrrole derivative and the one or more dyslipidemic agents, antiobesity agents, antihyperglycaemic agents, anti-inflammatory agents or mixtures thereof are administered sequentially. 
     
     
         7 . A method for the treatment of cardiovascular diseases, Alzheimer's disease, obesity, diabetes or inflammatory diseases comprising:
 administering to a mammal in need thereof a therapeutically effective amount of the combination product or medicament of  claim 1 .